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BACKGROUND & AIMS: A systemic inflammatory response via host-tumor interactions is a cancer hallmark that plays a pivotal role in the pathogenesis of malnutrition and sarcopenia in patients with malignancies. Hochuekkito (TJ-41) is a traditional Japanese herbal medicine that modulates inflammation in patients with various chronic inflammatory diseases. However, the clinical efficacy of TJ-41 in patients with malignancies remains unclear. METHODS: We systemically analyzed chronological changes in levels of systemic inflammatory parameters, nutrition-related parameters, and body composition status in 99 patients who received TJ-41 treatment for more than 3 months. The cohort comprised 56 patients with gastrointestinal cancer (Cancer Cohort) and 43 with other diseases (Other Disease Cohort). We also performed in vivo experiments in mice to validate the clinical findings. RESULTS: Despite no significant changes in serum albumin concentration and prognostic nutrition index, the serum C-reactive protein (CRP) concentration significantly decreased in a time-dependent manner in all patients. However, the serum CRP concentration significantly decreased during TJ-41 treatment in the Cancer Cohort but not the Other Disease Cohort. Furthermore, downregulation of CRP during TJ-41 treatment occurred only in patients with metastases. The psoas muscle index, as a muscle quantity marker, was significantly lower in the CRP-increased group compared with the CRP-decreased group during TJ-41 treatment. In vivo experiments using a Colon-26 syngeneic model showed that the plasma CRP, amyloid A, and interleukin-6 concentrations were significantly lower in the TJ-41 group than the control group. CONCLUSION: TJ-41 might be useful as part of multimodality therapy for gastrointestinal cancer, especially in patients with metastases.
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The present study investigated the effects of dietary supplementation combined with fish oil containing relatively low levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the inflammatory and nutritional status of patients with epithelial cancer. Fish oil capsules (498 mg EPA and 213 mg DHA) and dietary supplements (100 kcal and 5 g protein) were administered for 8 weeks to 20 patients with cancer and inflammation [C-reactive protein (CRP) ≥0.30 mg/dl]. Blood EPA levels increased significantly after 4 and 8 weeks, while no significant differences were observed in log-transformed (log) CRP levels, which were the major inflammatory indices in these patients. A declining trend was observed at 8 weeks after excluding 2 patients with suspected infection (P=0.06). A significant increase was observed from week 0 to week 8 for log interleukin-6 (IL-6) levels. After excluding the 2 patients with suspected infection, no significant difference was observed when comparing week 0 to week 8 for log IL-6. No deterioration in albumin or pre-albumin levels was observed. These results suggest that although suppression of acute inflammation associated with infection is difficult, intake of relatively low EPA and DHA supplements may be effective for mild chronic inflammation in patients with epithelial cancer without infection. Large-scale randomized clinical trials are required to make the final decision regarding efficacy. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; 06/07/2018, UMIN000033309).
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Previous studies have investigated the usefulness of microRNA (miRNA/miR) expression data for the early detection of colorectal cancer (CRC). However, limited data are available regarding miRNAs that detect CRC before clinical diagnoses. Accordingly, the present study investigated the early detectability of CRC by miRNAs using the preserved serum samples of the cohort participants affected with CRC within 2 years of study enrollment. First, the significant miRNAs were revealed using clinical CRC samples for a (seven early CRCs and seven controls) microarray analysis based on significance analysis of microarrays. Next, replicability was verified by reverse transcription-quantitative (RT-q)PCR (eight early CRCs and eight controls, together with 12 CRCs and 12 controls). Finally, early detectability was tested using the cohort samples of Japan Multi-Institutional Collaborative Cohort Study (17 CRCs and 17 controls) to reveal how a certain number of patients developed CRC within 2 years after participation. In the discovery phase, miRNA expression measurements were conducted using a 3D-Gene Human miRNA Oligo Chip for 2,555 miRNAs, and RT-qPCR analyses were performed to validate the replicability. In the first validation set with eight CRCs with early clinical stage and eight age- and gender-matched controls, miR-26a-5p and miR-223-3p demonstrated the highest diagnostic accuracy of area under the curve (AUC)=1.000 (sensitivity and specificity 100%). In an examination of the predictability of CRC incidence using pre-clinical cohort samples, miR-26a-5p demonstrated good predictability of advanced CRC incidence with an AUC of 0.840. Overall, the present study revealed serum miR-26a-5p as a potential early detection marker for CRC.
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BACKGROUND: Systemic inflammation via host-tumor interactions is currently recognized as a hallmark of cancer. The aim of this study was to evaluate the prognostic value of various combinations of inflammatory factors using preoperative blood, and to assess the clinical significance of our newly developed inflammatory score in colorectal cancer (CRC) patients. METHOD: In total 477 CRC patients from the discovery and validation cohorts were enrolled in this study. We assessed the predictive impact for recurrence using a combination of nine inflammatory markers in the discovery set, and focused on lymphocyte-C-reactive protein ratio (LCR) to elucidate its prognostic and predictive value for peri-operative risk in both cohorts. RESULTS: A combination of lymphocytic count along with C-reactive protein levels demonstrated the highest correlation with recurrence compared with other parameters in CRC patients. Lower levels of preoperative LCR significantly correlated with undifferentiated histology, advanced T stage, presence of lymph node metastasis, distant metastasis, and advanced stage classification. Decreased preoperative LCR (using an optimal cut-off threshold of 6000) was an independent prognostic factor for both disease-free survival and overall survival, and emerged as an independent risk factor for postoperative complications and surgical-site infections in CRC patients. Finally, we assessed the clinical feasibility of LCR in an independent validation cohort, and confirmed that decreased preoperative LCR was an independent prognostic factor for both disease-free survival and overall survival, and was an independent predictor for postoperative complications and surgical-site infections in CRC patients. CONCLUSION: Preoperative LCR is a useful marker for perioperative and postoperative management of CRC patients.
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Biomarcadores Tumorais/sangue , Proteína C-Reativa/metabolismo , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Linfócitos/metabolismo , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: In dialysis patients, malnutrition is a poor prognostic factor. In patients with chronic kidney disease (CKD), malnutrition is qualitatively different from general malnutrition, which is defined as "Protein-Energy Wasting (PEW)." Dietary therapy for the enhancement of PEW requires the aggressive intake of protein. Conversely, as protein intake and phosphorus intake correlate positively, increasing the protein intake increases the phosphorus intake, which is a poor prognostic factor in dialysis patients. One of the treatments for hyperphosphatemia in dialysis patients is the intake restriction of phosphorus by dietary counseling. However, protein uptake to maintain and augment the nutritional status and the protein intake restriction to correct hyperphosphatemia are contradictory treatments. Hence, this study aims to investigate the effects of PEW and hyperphosphatemia on the prognosis in hemodialysis patients. METHODS: We enrolled 60 outpatients who underwent maintenance hemodialysis for 6 months (May-November 2012) at Iga City General Hospital (Mie, Japan). In November 2012, we assessed the presence or absence of PEW and hyperphosphatemia in patients and evaluated the survival rate over the next 5 years. RESULTS: Overall, 10 patients (17%) were diagnosed as PEW. While 17 patients (28%) exhibited average phosphorus level >6.0 mg/dL (hyperphosphatemia). The 5-year survival rate was 30% in the PEW group, 66% in the non-PEW group, 57% in the hyperphosphatemia group, and 61% in the non-hyperphosphatemia group. A statistically significant difference existed between the PEW and non-PEW groups (P = 0.021). However, we observed no significant difference between the hyperphosphatemia and non-hyperphosphatemia groups. CONCLUSIONS: This study suggests that PEW affects the prognosis more than hyperphosphatemia in maintenance hemodialysis patients. The normalization of the serum phosphorus level by the protein intake restriction could prevent secondary hyperparathyroidism and vascular calcification. Conversely, restricting the protein intake poses a risk of malnutrition. In fact, early death occurred in patients with PEW in this study. Perhaps, patients with PEW should prioritize improving their nutritional status rather than controlling the serum phosphorus level.
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Caquexia/complicações , Hiperfosfatemia/complicações , Desnutrição Proteico-Calórica/complicações , Diálise Renal , Insuficiência Renal Crônica/complicações , Idoso , Índice de Massa Corporal , Ingestão de Alimentos , Feminino , Seguimentos , Humanos , Hiperfosfatemia/diagnóstico , Japão , Masculino , Desnutrição , Pessoa de Meia-Idade , Estado Nutricional , Prognóstico , Desnutrição Proteico-Calórica/diagnóstico , Desnutrição Proteico-Calórica/dietoterapia , Taxa de SobrevidaRESUMO
Treatment of cancer patients undergoing chemotherapy with L-carnitine (LC) supplementation is becoming increasingly popular in the clinic. The present study aimed to examine the possible effects of polymorphisms in CPT1B and CPT2 (CPT1B G320D, S427C, c.282-18 C>T, and p.E531K, and CPT2 V368I) on the plasma concentration of carnitine in humans. The subjects were the 218 participants of the Iga Cohort Study. Differences in plasma-free carnitine levels by genotype were examined. Genotyping was conducted by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The plasma carnitine levels were significantly higher in males (P<0.001; Student's t-test), and there was no significant difference in plasma carnitine levels between the age groups (P=0.202; ANOVA). One-way ANOVA revealed the plasma levels of carnitine were neither significantly different by CPT1B G320D, S427C, c.282-18 C>T, or p.E531K, nor by CPT2 V368I genotypes (P=0.133, P=0.538, P=0.636, P=0.509, and P=0.398, respectively). When analysis of covariance (ANCOVA) adjusted for age and sex was applied, the plasma levels of carnitine were not statistically significantly different according to these genotypes (P=0.299, P=0.715, P=0.980, P=0.851, and P=0.674, respectively). The present study did not identify any statistically significant differences in plasma carnitine levels between subjects with different CPT1 and CPT2 genotypes, suggesting that there may be no need to tailor treatments to patients' genotypes when determining the dose/amount of LC to be administered to cancer patients undergoing palliative care.
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Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina/sangue , Neoplasias/genética , Polimorfismo Genético/genética , Genótipo , Humanos , Neoplasias/metabolismoRESUMO
Gastrointestinal cancer is one of the most common causes of mortality globally. The present study examined the influence of cytokine genetic polymorphisms [interleukin (IL)-1B C-31T, IL-1RN VNTR, IL-6 C-634G, IL-8 T-251A, IL-10 T-819C and IL-10 A-1082G] on clinical outcomes in patients with gastrointestinal cancer in palliative care. A total of 59 patients with gastrointestinal cancer who were admitted to Iga City General Hospital were analyzed. Genotyping was conducted using a polymerase chain reaction with confronting two-pair primers. Patients with at least one IL-1RN 2 allele demonstrated a significantly better survival (P=0.0275) while those with IL-6-634 G/G demonstrated a worse survival (P=0.0024). Multivariate analyses using the Cox proportional hazard model revealed that those with at least one IL-1RN 2 allele, IL-6-634 G/G or IL-10-1082 A/G had a significantly elevated adjusted hazard ratio of 9.20 (P=0.014), 41.01 (P=0.001) or 6.49 (P=0.046), respectively, compared with those with each homozygous wild-type polymorphism. In addition, the evaluation of weight loss by genotype revealed the potential influence of IL-10 T-819C genotype (P=0.072). IL-1RN, IL-6 and IL-10 polymorphisms were associated with the survival of patients with gastrointestinal cancer, suggesting the clinical feasibility of genetic testing in patients with gastrointestinal cancer in palliative care.
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We used clinical data from Iga General Hospital to examine the association between polymorphisms in MTR (methionine synthase) A2756G (rs1805087), MTRR (methionine synthase reductase) His595Tyr (rs10380), MTHFR (methylenetetrahydrofolate reductase) C677T (rs1801133), MTHFR A1298C (rs1801131) and SHMT (serine hydroxymethyltransferase) C1420T (rs1979277), which are genes involved in folate metabolism, and the risk of weight loss in patients with gastrointestinal cancers, with the aim of establishing personalized palliative care for each patient based on genetic information. The data from 59 patients (37 males and 22 females) with gastrointestinal cancers who visited the outpatient clinic for cancer chemotherapy and palliative care at Iga General Hospital from December 2011 to August 2015 were analyzed. There was no significant association between the single nucleotide polymorphisms (SNPs) in the folate metabolizing genes examined and weight loss defined as weight loss of more than 5 percent or more than 10 percent during the first 6 months after initiation of chemotherapy. We did not detect any significant association between any of the SNPs examined and overall survival of patients. The present study indicated that these SNPs have relatively limited or no roles in the genesis of cachexia in patients with gastrointestinal cancers; however, further investigations into the roles of these folate metabolizing genes in the context of cancer palliative care, from clinical, biological and epidemiological viewpoints are warranted.
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Caquexia/genética , Gastroenteropatias/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Ferredoxina-NADP Redutase/genética , Predisposição Genética para Doença/genética , Glicina Hidroximetiltransferase/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIM: This study aimed to clarify the potential of modified Glasgow Prognostic Score (mGPS) as a prognostic biomarker and reveal the significance of fish oil (FO)-enriched nutrition in colorectal cancer (CRC). PATIENTS AND METHODS: A total of 738 CRC patients from three different patient cohorts, including 670 patients in the biomarker study and 68 patients in the nutrition-intervention study, were analyzed. RESULTS: High preoperative mGPS was significantly correlated with well-recognized disease progression factors and advanced UICC stage classification. In addition, high mGPS was an independent prognostic factor in both cohorts, especially in stage III and IV patients. These statuses were maintained in postoperative course and correlated with sarcopenia. Furthermore, FO-enriched nutrition suppressed systemic inflammatory reaction and improved skeletal muscle mass and prognosis, especially in CRC patients with mGPS 1 or 2. CONCLUSION: Assessment of mGPS could identify patients with high-risk CRC, who might be candidates for FO-enriched nutrition.
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Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Proteína C-Reativa/análise , Antígeno Carcinoembrionário/sangue , Estudos de Coortes , Neoplasias Colorretais/sangue , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Prognóstico , Albumina Sérica/análiseRESUMO
Serum transthyretin (TTR), also known as prealbumin, is a reliable nutritional indicator and an independent prognostic factor for maintenance hemodialysis patients. However, we recently reported that serum TTR levels did not affect protein-energy wasting (PEW). In this study, we investigated factors affecting serum TTR levels in 60 maintenance hemodialysis patients. The patients were divided into High-TTR and Low-TTR groups according to the median serum TTR level. Albumin levels were significantly higher and C-reactive protein (CRP) levels were significantly lower in the High-TTR group than in the Low-TTR group. Although body fat mass was significantly higher in the High-TTR group than in the Low-TTR group, no significant difference in body fat ratio were observed. These findings suggest that body fat mass is related to serum TTR levels, apart from factors such as albumin and CRP levels, which showed correlations with serum TTR levels. Because body fat mass is related to better survival in maintenance hemodialysis patients, it may contribute to the prognostic value of serum TTR levels. In addition, in such patients, it may be important to evaluate body fat mass rather than body fat ratio and to maintain the minimum necessary body fat mass. J. Med. Invest. 64: 222-227, August, 2017.
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Tecido Adiposo/metabolismo , Pré-Albumina/análise , Diálise Renal , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/mortalidade , Albumina Sérica/análiseRESUMO
Despite recent advances in chemotherapy for gastrointestinal cancer, a crucial factor related to poor prognosis is reduced tolerance to chemotherapy induced by cancer cachexia. Fish oil (FO)-derived eicosapentaenoic acid (EPA) modulates inflammation in patients with various malignancies; however, the impact of FO-enriched nutrition as a combined modality therapy on clinical outcomes remains controversial. We systemically analysed chronological changes in biochemical and physiological status using bioelectrical impedance analysis in 128 gastrointestinal cancer patients provided with or without FO-enriched nutrition during chemotherapy. Furthermore, we evaluated the clinical significance of FO-enriched nutrition and clarified appropriate patient groups that receive prognostic benefits from FO-enriched nutrition during treatment of gastrointestinal cancer. The control group showed significant up-regulation of serum CRP) levels and no significant difference in both skeletal muscle mass and lean body mass. In contrast, the FO-enriched nutrition group showed no changes in serum CRP concentration and significantly increased skeletal muscle mass and lean body mass over time. Furthermore, high CRP levels significantly correlated with reduced tolerance to chemotherapy, and FO-enriched nutrition improved chemotherapy tolerance and prognosis, particularly in gastrointestinal cancer patients with a modified Glasgow prognostic score (mGPS) of 1 or 2. We conclude that FO-enriched nutrition may improve the prognosis of patients with cancer cachexia and systemic inflammation (i.e., those with a mGPS of 1 or 2).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Caquexia/dietoterapia , Gorduras Insaturadas na Dieta/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Óleos de Peixe/administração & dosagem , Neoplasias Gastrointestinais/dietoterapia , Idoso , Antígenos Glicosídicos Associados a Tumores/sangue , Composição Corporal , Proteína C-Reativa/metabolismo , Caquexia/tratamento farmacológico , Caquexia/mortalidade , Caquexia/patologia , Antígeno Carcinoembrionário/sangue , Estudos de Coortes , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Humanos , Inflamação , Masculino , Estado Nutricional , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: In palliative care, prediction of life expectancy is one of the most crucial issues for patients, family and medical staff, in order to provide appropriate end-of-life care. The aim of this study was to formulate a new objective score to predict life expectancy within 1 week for terminally ill patients with cancer. PATIENTS AND METHODS: Medical records were obtained from 187 terminally-ill patients with cancer who were admitted for palliative care. The biomarkers for a potential 'Objective Predictive Score' were assessed. RESULTS: Profiling of blood parameters demonstrated that elevated levels of alanine aminotransferase (ALT), total bilirubin (T-bil), blood urea nitrogen (BUN), creatinine (Cr) and a decreased platelet count were significantly correlated with death within 1 week in a training cohort. Our formulated Objective Predictive Score was able to predict death within 1 week with high accuracy in a training and a validation cohort. CONCLUSION: Our scoring system might enable the assessment of prognostication with higher accuracy in a terminal care setting.
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Neoplasias/sangue , Índice de Gravidade de Doença , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Bilirrubina , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Feminino , Humanos , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Cuidados Paliativos , Contagem de Plaquetas , Prognóstico , Modelos de Riscos Proporcionais , Assistência Terminal , Doente TerminalRESUMO
BACKGROUND AND OBJECTIVES: The International Society of Renal Nutrition and Metabolism (ISRNM) has recently recommended the use of the term "protein-energy wasting" (PEW). PEW is a state of malnutrition with decreased body stores of protein and energy fuel in hemodialysis patients and is known as a risk factor for morbidity and mortality. We examined the prevalence of PEW and the characteristics of PEW patients in a hemodialysis center in Japan. METHODS AND STUDY DESIGN: Fifty-nine outpatients undergoing maintenance hemodialysis at Iga City General Hospital were evaluated. We observed their biochemical data, body composition, dietary intake, and the number of steps prospectively. PEW was defined according to ISRNM criteria. RESULTS: Nine patients (15% of total) were diagnosed as having PEW. Among indicators of PEW criteria, the relevance ratios of "reduced muscle mass" and "unintentional low dietary energy intake" were significantly higher in PEW than in non-PEW. The number of steps was lower, and serum levels of glucose and C-reactive protein were higher in PEW. CONCLUSION: About 15% of Japanese hemodialysis patients are estimated to have PEW. Our results suggested that major contributing factors to PEW were reduced muscle mass, unintentional low dietary energy intake, lower amount of exercise, insulin resistance, and chronic inflammation.